Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term treatment of breast cancer patients with tamoxifen has prompted concern over potential toxicity of this drug with chronic administration. Since tamoxifen has estrogenic action in the rat liver and estrogenic agents can increase hepatoma incidence in rats, tamoxifen and two non-isomerizable, fixed-ring analogs (FRT1 and FRT2) were evaluated as promoting agents in a two-stage model of hepatocarcinogenesis in female Fischer F344 rats. The rats were subjected to 70% partial hepatectomy and half of the animals were administered the initiating agent, diethylnitrosamine (DEN; 10 mg/kg body wt), while the other half were not initiated. Groups of initiated and uninitiated animals were allowed to recover for 2 weeks and were then administered tamoxifen or one of the fixed-ring analogs admixed into AIN-76A diet at 25, 100 or 250 mg/kg diet. After 6 months of anti-estrogen administration the rats were sacrificed and uterine weights, blood levels of anti-estrogen, and liver histopathology were assessed. Uterine weights were decreased 2- to 3-fold by each of the agents, consistent with an anti-estrogenic action in the rat. The serum levels in rats administered 250 mg anti-estrogen/kg diet for 6 months were 320+/-20 ng/ml for tamoxifen, 320+/-10 for FRT1 and 350+/-20 for FRT2. The liver levels after a 6 month administration of 250 mg anti-estrogen/kg diet were 13 870+/-860 ng/g for tamoxifen, 13 300 +/-860 for FRT1 and 26 900+/-1900 for FRT2. A dose-dependent increase in serum and liver level of each compound was noted when measured at the 6 month time period. The number and percentage of the liver occupied by altered hepatic foci (AHF) were determined by quantitative stereology. A dose-dependent increase above initiated controls was observed in the initiated, tamoxifen-treated rats. Both fixed-ring analogs also increased the number and size of AHF compared with initiated controls, but were less potent than tamoxifen, suggesting that tamoxifen has an intrinsic promoting action in the liver that is independent of its ability to isomerize to more potent estrogenic compounds. In addition, the fixed-ring analogs have a weaker promoting activity in the rat liver than does tamoxifen. This may be due to pharmacokinetic differences at the lower two doses, but it is independent of achieved serum level at the highest dose and hence may reflect differences in intrinsic activity of these compounds. Thus tamoxifen and the two fixed-ring analogs promote the development of rat hepatocarcinogenesis.
Carcinogenesis 1996 Mar
PMID:The effect of tamoxifen and two of its non-isomerizable fixed-ring analogs on multistage rat hepatocarcinogenesis. 863 Nov 49

FRAT1 positively regulates the WNT signaling pathway by stabilizing beta-catenin through the association with glycogen synthase kinase-3beta. Here, we have cloned FRAT2 cDNAs, spanning the complete coding sequence, from a human fetal lung cDNA library. FRAT2 encoded 233 amino-acid protein, which showed 77.3% total amino-acid identity with FRAT1. FRAT2 and FRAT1 were more homologous in the acidic domain (96% identity), the proline-rich domain (92% identity), and the GSK-3beta binding domain (100% identity). The FRAT2 gene was mapped to human chromosome 10q24.1. The FRAT2 mRNA of 2.4-kb in size was relatively highly expressed in MKN45 (gastric cancer), HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). Xenopus axis duplication assay revealed that the wild-type FRAT2 mRNA, but not the mutant FRAT2 mRNA lacking the acidic domain and the proline-rich domain, has the capacity to induce the secondary axis. These results indicate that FRAT2, just like FRAT1, functions as a positive regulator of the WNT signaling pathway. Thus, up-regulation of FRAT2 in human cancer might be implicated in carcinogenesis through activation of the WNT signaling pathway.
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PMID:Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway. 1123 32

FRAT1 and FRAT2 are cancer-associated genes encoding GSK-3beta-binding proteins. Over-expression of FRAT1 or FRAT2 lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway. We have previously cloned and characterized FRAT2. Here, we found that FRAT1 and FRAT2 genes were clustered in the human chromosome 10q24.1 region. Blast search revealed that FRAT1 and FRAT2 genes, consisting of a single exon, were located together on human genome draft sequences AC006098.1 and AL355490.7, corresponding to the human chromosome 10q24.1 region. FRAT1 and FRAT2 genes were clustered in a tail to tail manner with an interval of about 10.7 kb. The 2.7-kb FRAT1 mRNA was relatively highly expressed in fetal brain, adult spleen, pancreas, HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). FRAT1 and FRAT2 were co-expressed in 7 gastric cancer cell lines and 10 cases of primary gastric cancer, and were up-regulated together in gastric cancer cell line TMK1 and 2 cases of primary gastric cancer. These results indicated that FRAT1 and FRAT2 genes were up-regulated together in several cases of human gastric cancer. Up-regulation of FRAT1 and FRAT2 in gastric cancer might lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway.
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PMID:FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. 1144 44

FRAT1 and FRAT2 genes, clustered in human chromosome 10q24, are human homologues to mouse proto-oncogene Frat1, which promotes carcinogenesis through activation of the WNT - beta-catenin - TCF signaling pathway. FRAT1 and FRAT2 mRNAs are up-regulated together in a gastric cancer cell line TMK1, and also in 2 out of 10 cases of primary gastric cancer. Here, we isolated FRAT1 cDNA (AB074890), which showed two amino-acid substitutions (Gln57X and His58Asp) compared with human FRAT1 cDNA previously reported by another group (U58975). The Gln57-His58 FRAT1 allele isolated in this study was also identified in human genome draft sequences. FRAT1 mRNA was almost ubiquitously expressed in human pancreatic cancer cell lines. Expression level of FRAT1 mRNA was relatively higher in esophageal cancer cell lines TE2, TE3, TE4, a cervical cancer cell line SKG-IIIa, and breast cancer cell lines MCF-7 and T-47D. Expression level of FRAT1 mRNA was not significantly changed after all-trans retinoic-acid treatment in NT2 cells with the potential of neuronal differentiation. Expression of FRAT1 mRNA in MCF-7 cells derived from breast cancer was down-regulated by beta-estradiol. This is the first report on isolation of FRAT1 cDNA derived from the more common FRAT1 allele, and also on regulation of FRAT1 mRNA in human cancer cells.
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PMID:Molecular cloning and expression of proto-oncogene FRAT1 in human cancer. 1189 25

WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse Wnt3a-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.
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PMID:WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). 1201 73

The biological functions of some orthologs within the human genome and model-animal genomes are evolutionarily conserved, but those of others are divergent due to protein evolution and promoter evolution. Because WNT signaling molecules play key roles during embryogenesis, tissue regeneration and carcinogenesis, the author's group has carried out a human WNT-ome project for the comprehensive characterization of human genes encoding WNT signaling molecules. From 1996 to 2002, we cloned and characterized WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT9A/WNT14, WNT9B/WNT14B, WNT10A, WNT10B, WNT11, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1, RHOU/ARHU, RHOV/ARHV, GIPC2, GIPC3, FBXW11/betaTRCP2, SOX17, TCF7L1/TCF3, and established a cDNA-PCR system for snap-shot and dynamic analyses on the WNT-transcriptome. In 2003, we identified and characterized PRICKLE1, PRICKLE2, DACT1/DAPPER1, DACT2/DAPPER2, DAAM2, and BCL9L. After completion of the human WNT-ome project, we have been working on the stem cell signaling network. WNT signals are transduced to beta-catenin, NLK, NFAT, PKC, JNK and RhoA signaling cascades. FGF20, JAG1 and DKK1 are target genes of the WNT-beta-catenin signaling cascade. Cross-talk of WNT and FGF signaling pathways potentiates beta-catenin and NFAT signaling cascades. BMP signals induce IHH upregulation in co-operation with RUNX. Hedgehog signals induce upregulation of SFRP1, JAG2 and FOXL1, and then FOXL1 induces BMP4 upregulation. The balance between WNT-FGF-Notch and BMP-Hedgehog signaling networks is important for the maintenance of homoestasis among stem and progenitor cells. Disruption of the stem cell signaling network results in pathological conditions, such as congenital diseases and cancer.
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PMID:Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. 1787 79